Infection with the bacteria Porphyromonas gingivalis has been linked to the development of periodontal disease, Alzheimer's and other brain disorders, cardiovascular disease, diabetes, cancer, liver disease, kidney disease, preterm birth, arthritis, pneumonia and other disorders. P. gingivalis is an anaerobic asaccharolytic gram-negative rod bacterium that is known to infect the oral cavity and translocate systemically into coronary arteries, aorta, placental tissue, the brain, the kidneys, and the liver. The bacterium has also been identified in cancerous tissues and a mechanism has been proposed by which gingipains can trigger immortalization and metastasis. See: Gandhimadhi, et al. Journal of Indian Society of Periodontology. 2010; 14(2):114-120; Liao, et al., Med Hypotheses, 2009. 72(6): 732-5; Byme, et al., Oral Microbiol Immunol, 2009. 24(6): 469-77; Mahendra, et al., J Maxillofac Oral Surg, 2009. 8(2): 108-13; Stelzel, et al., J Periodontol, 2002. 73(8): 868-70; Katz, et al., Journal of Dental Research, 2009. 88(6): 575-578; Poole, et al., J Alzheimers Dis, 2015, 43(1): 67-80; Ishikawa, et al., Biochim Biophys Acta, 2013. 1832(12): 2035-2043; Inaba, et al., Cellular Microbiology, 2014. 16(1): 131-145.
P. gingivalis produces extracellular proteases called gingipains, including Arginine Gingipain A (RgpA), Arginine Gingipain B (RgpB) and Lysine Gingipain (Kgp). Gingipains contribute to many functions of the organism including its survival and virulence. Gingipains can be secreted, transported to outer membrane surfaces of P. gingivalis, or released in outer membrane vesicles by the bacterium. Gingipains degrade a broad range of proteins (e.g., immunoglobulins, proteinase inhibitors, actin, and collagen) which can lead to cytoskeleton collapse and apoptosis in many types of cells. Recent research has demonstrated that small, peptide-derived inhibitors of Kgp can prevent gingipain-induced epithelial cell death. See: Travis, et al., Adv Exp Med Biol, 2000. 477: 455-65; Sheets, et al., Infect Immun, 2005. 73(3): 1543-52; Sheets, et al., Infect Immun, 2006. 74(10): 5667-78; Stathopoulou, et al., BMC Microbiol, 2009. 9: 107. New compounds for the inhibition of gingipain activity and the treatment of diseases associated with gingipain activity and P. gingivalis infection are needed. The present invention addresses this and other needs.